Kinases are a class of enzyme that control the transfer of phosphate groups from phosphate donor groups, for example ATP, to specific substrates. Protein kinases are a subset of kinases and BTK is one such protein kinase.
BTK is a member of the src-related Tec family of cytoplasmic tyrosine kinases. BTK plays a key role in the signalling pathways of B-cells, affecting B-cell development, activation, signalling and survival. In certain malignancies, B-cells overexpress BTK. These malignant B-cells and the overexpression of BTK by the cells has been associated with the increased proliferation and survival of tumor cells. Inhibition of BTK affects the B-cell signalling pathways, preventing activation of B-cells and inhibiting the growth of malignant B-cells.
A number of clinical trials have shown that BTK inhibitors are affective against cancer.
BTK inhibitors that have been reported are Ibrutinib (PCI-32765) and CC-292. CC-292 is manufactured by Avila Pharmaceuticals who have filed applications for protein kinases published as WO 2011/090760 and WO 2009/158571. Ibrutinib is disclosed in at least US 2008/0076921. Studies on Ibrutinib have found that it possesses a number of undesirable pharmacological features. For example, Ibrutinib is poorly soluble and is a weak inhibitor of hERG. Furthermore, rat pharmacokinetic data has shown that Ibrutinib has a low estimated fraction absorbed, poor bioavailability and a high clearance rate from the body, with a terminal T1/2 of 1.5 hours.
Since Ibrutinib was first disclosed there have been a number of patent applications concerned with structures closely related to Ibrutinib, for example see WO 2012/158843, WO 2012/158764, WO 2011/153514, WO 2011/046964, US 2010/0254905, US 2010/0144705, U.S. Pat. No. 7,718,662, WO, 2008/054827 and WO 2008/121742.
Most recently, WO 2013/010136 disclosed BTK inhibitors with a related structure to Ibrutinib.
Known BTK inhibitors, e.g. Ibrutinib, have presented gastrointestinal side effects. These side effects have been attributed to the EGFR inhibitory activity of the BTK inhibitors. It is therefore desirable to have a BTK inhibitor with high BTK inhibition and low EGFR inhibition to reduce or avoid the gastrointestinal side effects. Such high BTK inhibition and low EGFR inhibition is readily identified by a large “Fold Selectivity” value.
Therefore, an aim of the present invention is to provide BTK inhibitors. In addition the invention aims to provide BTK inhibitors with high selectivity for BTK inhibition over EGFR inhibition.
Furthermore, it is an aim of certain embodiments of this invention to provide new cancer treatments. In particular, it is an aim of certain embodiments of this invention to provide compounds which have comparable activity to existing cancer treatments, ideally they should have better activity. Certain embodiments of the invention also aim to provide improved solubility compared to prior art compounds and existing therapies. It is particularly attractive for certain compounds of the invention to provide better activity and better solubility over known compounds.
It is an aim of certain embodiments of this invention to provide compounds which exhibit reduced cytotoxicity relative to prior art compounds and existing therapies.
Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing. A further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).
Certain embodiments of the present invention satisfy some or all of the above aims.